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Anti-TNF agents restrict AIEC replication within macrophages in patients with Crohn’s disease.

kiny

Well-known member
https://academic.oup.com/ecco-jcc/a...o-jcc/jjab236/6504016?redirectedFrom=fulltext

12 January 2022

Université Clermont Auvergne, France.

Clara Douadi, Emilie Vazeille, Christophe Chambon, Michel Hébraud, Margot Fargeas, Marie Dodel, Dilek Coban, Bruno Pereira, Aurélien Birer, Pierre Sauvanet, Anthony Buisson, Nicolas Barnich

Anti-TNF agents restrict adherent-invasive Escherichia coli replication within macrophages through modulation of chitinase 3-like 1 in patients with Crohn's disease

Background & aims:

The mechanism of action of anti-TNF agents could implicate macrophages modulation in Crohn's disease (CD). As CD macrophages are defective to control CD-associated adherent-invasive E. coli (AIEC), anti-TNF agents could limit AIEC replication within macrophages. We assessed the effect of anti-TNF agents on AIEC survival within monocytes-derived macrophages (MDM) from CD patients and attempted to identify the implicated proteins.

Methods:
Peripheral blood monocyte-derived macrophages (MDM) were obtained from 44 CD patients including 22 with and 22 without anti-TNF agents. MDM were infected with AIEC-LF82 reference strain. Proteomic analysis was performed before and 6h after AIEC-LF82 infection.

Results:
AIEC-LF82 survival was lower in MDM from CD patients receiving anti-TNF agents compared to those who did not (-73%, p=0.006). After AIEC-LF82 infection, the levels of CD82 (p=0.007), ILF3 (Interleukin enhancer-binding factor 3; p=0.001), FLOT-1 (Flotillin-1; p=0.007) and CHI3L1 (Chitinase 3-like 1; p=0.035) proteins were different within CD-MDM depending on anti-TNF exposure. FLOT-1 (ϱ=- 0.44; p=0.038) and CHI3L1 (ϱ=0.57, p=0.006) levels were inversely and positively correlated with AIEC survival within MDM from CD patients with or without anti-TNF, respectively. We observed a dose-dependent decrease of AIEC-LF82 survival after adjunction of anti-TNF within MDM inducing increase of FLOT-1 and decrease of CHI3L1 mRNA levels. Neutralization of intra-macrophagic CHI3L1 protein using anti-CHI3L1 antibodies reduced AIEC survival within macrophages 6h after infection (p<0.05).

Conclusion:
Anti-TNF agents are able to restrict replication of pathobiont, such as AIEC, within macrophages by modulating FLOT-1 and CHI3L1 expressions in CD patients.
 

Scipio

Well-known member
Location
San Diego
"Anti-TNF agents restrict adherent-invasive Escherichia coli replication within macrophages through modulation of chitinase 3-like 1 in patients with Crohn's disease"

Can anyone (except for me) turn the title above into everyday English?
To understand the title you need a little background information: adherent E. coli bacteria (AIEC), which are suspected to play a role in causing Crohn's disease in some patients, partially evade the immune system by hiding out inside a certain type of the host's white blood cells (macrophages) that have engulfed them and by replicating themselves inside those cells.

So this research is saying that anti-TNF drugs (primarily Remicade and Humira) have the beneficial effect of decreasing the ability of the AIEC to reproduce inside those cells by decreasing the activity of certain enzymes that promote the reproduction of the bacteria.

This is interesting news because anti-TNF drugs are thought to primarily exert their benefical effects by blocking the action of TNF - a protein that stimulates the immune system. This study suggests that the drugs also have further beneficial effects by a quite different mechanism. And it also further implicates AIEC infection as a possible trigger for Crohn's.
 
Last edited:
To understand the title you need a little background information: adherent E. coli bacteria (AIEC), which are suspected to play a role in causing Crohn's disease in some patients, partially evade the immune system by hiding out inside a certain type of the host's white blood cells (macrophages) that have engulfed them and by replicating themselves inside those cells.

So this research is saying that anti-TNF drugs (primarily Remicade and Humira) have the beneficial effect of decreasing the ability of the AIEC to reproduce inside those cells by decreasing the activity of certain enzymes that promote the reproduction of the bacteria.

This is interesting news because anti-TNF drugs are thought to primarily exert their benefical effects by blocking the action of TNF - a protein that stimulates the immune system. This study suggests that the drugs also have further beneficial effects by a quite different mechanism. And it also further implicates AIEC infection as a possible trigger for Crohn's.
Woah, does it speak more to the power of this bacteria or the weakness of the white blood cells? Essentially this bacteria uses the white cells to duplicate itself and somehow can break out of the whites?
 

Scipio

Well-known member
Location
San Diego
Woah, does it speak more to the power of this bacteria or the weakness of the white blood cells? Essentially this bacteria uses the white cells to duplicate itself and somehow can break out of the whites?
Both perhaps. Some microorganisms can live more or less forever inside of white blood cells - HIV for example and some herpes viruses too. One theory for a major contributing cause of Crohn's is that these white blood cells have a genetic defect in some people that allows the bacteria to be engulfed but not killed. And the constant presence of the bacteria infecting the cells triggers the chronic inflammation that wrecks the nearby gut tissue. It would explain how the apparent genetic component to Crohn's susceptibility works and why some people get Crohn's but most don't - it's more than just diet or infection; there must also be this genetic defect that allows the bacterial infection to persist.

A good theory IMO but not yet proven. The main thing telling against it is that there are plenty of Crohn's cases (such as mine) where the genes known to confer Crohn's susceptibility (NOD2 for example) are not present. So genes may be only one of several factors that can interact in various permutations to trigger a case of Crohn's. IMO, there is no one big cause of Crohn's. There are multiple sub-causes that can add up to a case of Crohn's by different inter-related routes.
 
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